Roles of free fatty acid macrophage mediated killing of mycobacteria

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We previously reported that reactive nitrogen intermediates and free fatty acid (FFA) play important roles in the expression of the activity of mouse peritoneal macrophages (Mφs) against Mycobacterium tuberculosis (MTB) and M. avium complex (MAC). In the present study, we examined the roles of phospholipase A_2 (PLA_2) which specifically releases arachidnic acid (AA) from membrane phospholipid in Mφantimycobacterial activity, and obtained the following results. (1) The intracellular growth of MTB residing in IFN-γ-activated Mφs was accelerated by the quinacrine (PLA_2 inhibitor) and a-TFMK (cPLA_2 inhibitor) (2) The radioactivity of MTB organisms, which were recovered from ^3H-AA loaded Mφs, was progressively increased during Mφ cultivation after MTB infection. Such a phenomenon was blocked when Mφs were treated quinacrine or a-TFMK, indicating that AA translocated to MTB within phagosome in a cPLA_2-dependent fashion. (3) The expression of cPLA_2 and iNO5 mRNAs was increased in IFN-γ- activated Mφ, this is not the case for sPLA_2 mRNA. (4) Fluorescence microscopy on infected Mφs stained with anti cPLA_2 antibody and pyrene labelled cPLA_2 substrates demonstrated that cPLA_2 translocated to mycobacterial organisms within the phagosomes of the Mφs. (5) In the case of mouse peritoneal Mφs, MAP kinase-dependent cPLA_2 phospholylation at the serine residues was observed in the early phase of Mφ cultivation after MTB infection, gradually increased at least for 48 h. On the other hand, constitutive phospholylation of cPLA_2 was observed in RAW Mφs regard less of MTB infection. These findings indicate that cPLA_2 plays important roles in the expression of antimicrobial activity of Mφs against MTB and MAC.